This invention relates to new RAR selective retinoid agonists and to the use of such retinoic acid receptor agonists, particularly retinoic acid receptor xcex3 (RARxcex3) selective agonists for the treatment of emphysema.
Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality, ranking third and fourth as the leading cause of death in the European Union and North America respectively. COPD is characterized by reduced maximum expiratory flow, which does not change over several months and which persists for 2 or more consecutive years. Patients with the most severe form of COPD generally present with a significant degree of emphysema. Emphysema is defined anatomically by permanent airspace enlargement distal to the terminal bronchioles. It is characterized by gradual loss of lung recoil, alveolar destruction, decreased alveolar surface area and gas exchange, leading to a reduced FEV1. These two features, impaired gas exchange and reduction in expiratory flow, are characteristic physiological abnormalities from which patients with emphysema suffer. The main symptom of patients with severe emphysema is shortness of breath during minimal physical activity.
The most common cause of emphysema is cigarette smoking although other potential environmental toxins may also contribute. These various insulting agents activate destructive processes in the lung including release of active proteases and free radical oxidants in excess of protective mechanisms. The imbalance in protease/anti-protease levels leads to destruction of the elastin matrix, loss of elastic recoil, tissue damage and continuous decline in lung function. Removing the injurious agents (i.e. quit smoking) slows the rate of damage, however, the damaged alveolar structures do not repair and lung function is not regained.
Retinoic acid is a multifunctional modulator of cellular behavior, having the potential to alter both extracellular matrix metabolism and normal epithelial differentiation. In lung, retinoic acid has been shown to modulate various aspects of lung differentiation by interacting with specific retinoic acid receptors (RAR) that are selectively expressed temporally and spatially. Coordinated activation of RARxcex2 and RARxcex3 has been associated with lung branching and alveolization/septation. During alveolar septation, retinoic acid storage granules increase in the fibroblastic mesenchyme surrounding alveolar walls and RARxcex3 expression in the lung peaks. Depletion of these retinyl-ester stores parallels the deposition of new elastin matrix and septation. In support of this concept, (Massaro et al., Am. J. Physiol., 1996, 270, L305-L310) demonstrated that postnatal administration of retinoic acid increases the number of alveoli in rats. Furthermore, the capacity of dexamethasone to prevent the expression of CRBP and RARxcex2 mRNA and subsequent alveolar septation in developing rat lungs was abrogated by all-trans retinoic acid.
Recent studies demonstrated that all-trans retinoic acid can induce formation of new alveoli and return elastic recoil to near normal in animal models of emphysema (D. Massaro et al. Nature Medicine, 1997, 3, 675). However, the mechanism by which this occurs remains unclear.
Retinoids are a class of compounds structurally related to vitamin A, comprising natural and synthetic compounds. Several series of retinoids have been found clinically useful in the treatment of dermatological and oncological diseases. Retinoic acid and its other naturally occurring retinoid analogs (9-cis retinoic acid, all-trans 3,4-didehydro retinoic acid, 4-oxo retinoic acid and retinol) are pleiotropic regulatory compounds that modulate the structure and function of a wide variety of inflammatory, immune and structural cells. They are important regulators of epithelial cell proliferation, differentiation and morphogenesis in lungs. Retinoids exert their biological effects through a series of hormone nuclear receptors that are ligand inducible transcription factors belonging to the steroid/thyroid receptor superfamily. The retinoid receptors are classified into two families, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), each consisting of three distinct subtypes (xcex1, xcex2, and xcex3). Each subtype of the RAR gene family encodes a variable number of isoforms arising from differential splicing of two primary RNA transcripts. All-trans retinoic acid is the physiological hormone for the retinoic acid receptors and binds with approximately equal affinity to all the three RAR subtypes, but does not bind to the RXR receptors for which 9-cis retinoic acid is the natural ligand.
In many non-pulmonary tissues, retinoids have anti-inflammatory effects, alter the progression of epithelial cell differentiation, and inhibit stromal cell matrix production. These properties have led to the development of topical and systemic retinoid therapeutics for dermatological disorders such as psoriasis, acne, and hypertrophic cutaneous scars. Other applications include the control of acute promyelocytic leukemia, adeno- and squamous cell carcinoma, and hepatic fibrosis. A limitation in the therapeutic use of retinoids outside of cancer has stemmed from the relative toxicity observed with the naturally occurring retinoids, all-trans retinoic acid and 9-cis retinoic acid. These natural ligands are non-selective and therefore have pleiotropic effects throughout the body, which are often toxic. Recently various retinoids have been described that interact selectively or specifically with the RAR or RXR receptors or with specific subtypes (xcex1, xcex2, xcex3) within a class.
Thus the retinoids according to the invention can further be used for the therapy and prophylaxis of dermatological disorders which are accompanied by epithelial lesions, e.g. acne and psoriasis, light- and age-damaged skin; as well as for the promotion of wound healing, for example of incised wounds, such as surgical wounds, wounds caused by burns and other wounds caused by cutaneous trauma; and for the therapy and prophylaxis of malignant and premalignant epithelial lesions, tumours and precancerous changes of the mucous membrane in the mouth, tongue, larynx, oesophagus, bladder, cervix and colon. In particular, the retinoids according to the invention promote repair of damaged alveoli.
This invention provides new RAR selective retinoid agonists of formula I 
wherein
R1 and R2 independently of each other are hydrogen or lower alkyl;
A is C(R5R6),
n is an integer 1, 2 or 3,
B is C(R3R4), oxygen, S(O)m or N-alkyl and
m is 0, 1 or 2; or
A is oxygen,
n is 1 and
B is C(R3R4);
X is xe2x80x94CR7xe2x80x2xe2x80x94 or nitrogen;
R3, R4, R5 and R6 independently of each other are hydrogen or lower alkyl;
R7 and R7xe2x80x2 independently of each other are hydrogen, alkyl, alkenyl, alkoxy, alkoxyalkyl, substituted alkyl, phenyloxy or substituted phenyloxy, or R7 and R7xe2x80x2 together are xe2x80x94(CH2)pxe2x80x94, where p is 2-6, with the proviso that when X is nitrogen then R7 is alkyl, alkoxyalkyl or substituted alkyl;
Z is xe2x80x94COOxe2x80x94, xe2x80x94OCOxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94CH2Oxe2x80x94, xe2x80x94CH2Sxe2x80x94, xe2x80x94OCH2xe2x80x94, xe2x80x94SCH2xe2x80x94, xe2x80x94COCH2xe2x80x94 or xe2x80x94CH2COxe2x80x94, with the provisos that when Z is xe2x80x94OCH2xe2x80x94, or xe2x80x94SCH2xe2x80x94, then X is xe2x80x94CR7xe2x80x2xe2x80x94, and that when Z is xe2x80x94Cxe2x89xa1Cxe2x80x94 then X is CR7xe2x80x2 and R7 is phenoxy or substituted phenoxy;
Ar is phenyl, substituted phenyl or a heteroarylic ring; and
R8 is hydrogen, lower alkyl or benzyl;
and pharmaceutically acceptable salts of carboxylic acids of formula I.
In one aspect, this invention provides new RAR selective retinoid agonists of formula I 
wherein
R1, R2 are independently of each other hydrogen or lower alkyl;
A represents C(R5R6) and
n is an integer 1, 2 or 3; or
A is oxygen and
n is 1;
B represents C(R3R4), oxygen, S(O)m or N-alkyl, with the proviso that when A is oxygen, then B is C(R3R4);
m is 0, 1 or 2;
X is xe2x80x94CR7xe2x80x2xe2x80x94 or nitrogen;
R3, R4, R5, R6 are independently of each other hydrogen or lower alkyl;
R7 and R7xe2x80x2 are independently of each other hydrogen, alkyl, alkenyl, alkoxy, alkoxyalkyl, substituted alkyl, phenyloxy or substituted phenyloxy, or R7 and R7xe2x80x2 together are xe2x80x94(CH2)pxe2x80x94, where p is 2-6, with the proviso that when X is nitrogen then R7 is alkyl, alkoxyalkyl or substituted alkyl;
Z is xe2x80x94COOxe2x80x94, xe2x80x94OCOxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94CH2Oxe2x80x94, xe2x80x94CH2Sxe2x80x94, xe2x80x94OCH2xe2x80x94, xe2x80x94SCH2xe2x80x94, xe2x80x94COCH2xe2x80x94 or xe2x80x94CH2COxe2x80x94, with the provisos that when Z is xe2x80x94OCH2xe2x80x94 or xe2x80x94SCH2xe2x80x94, then X is xe2x80x94CR7xe2x80x2xe2x80x94, and that when Z is xe2x80x94Cxe2x89xa1Cxe2x80x94 then X is CR7xe2x80x2 and R7 is phenoxy or substituted phenoxy;
Ar is phenyl, substituted phenyl or a heteroarylic ring; and
R8 is hydrogen, lower alkyl or benzyl;
and pharmaceutically active salts of carboxylic acids of formula I.
Especially preferred compounds of formula I are the compounds wherein
B represents C(R3R4), oxygen, S(O)m or Nxe2x80x94CH3, with the proviso that when A is oxygen, then B is C(R3R4);
R7 and R7xe2x80x2 are, independently of each other, hydrogen, alkyl, alkoxy, alkoxyalkyl, substituted alkyl or phenyloxy or substituted phenyloxy, with the proviso that when X is nitrogen then R7 is alkyl, alkoxyalkyl or substituted alkyl;
Z is xe2x80x94COOxe2x80x94, xe2x80x94OCOxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x89xa1CHxe2x80x94, xe2x80x94CH2Oxe2x80x94, xe2x80x94CH2Sxe2x80x94, xe2x80x94OCH2xe2x80x94, xe2x80x94SCH2xe2x80x94, xe2x80x94COCH2xe2x80x94 or xe2x80x94CH2COxe2x80x94, with the proviso that when Z is xe2x80x94OCH2xe2x80x94 or xe2x80x94SCH2xe2x80x94, then X is xe2x80x94CHxe2x80x94.
The term xe2x80x9calkylxe2x80x9d as used herein denotes straight or branched chain alkyl residues containing 1 to 10, preferably 1 to 7 carbon atoms, such as methyl, ethyl, isobutyl, pentyl, amyl, 3-pentyl, hexyl or heptyl. The term xe2x80x9clower alkylxe2x80x9d as used herein denotes alkyl residues as defined above, however, with 1 to 5 carbon atoms.
As used herein, the term xe2x80x9calkoxyxe2x80x9d refers to a straight or branched chain hydrocarbonoxy group wherein the xe2x80x9calkylxe2x80x9d portion is an alkyl group as defined above. Examples include methoxy, ethoxy, n-propyloxy and the like.
As used herein, the term xe2x80x9calkoxyalkylxe2x80x9d refers to an ether group wherein the xe2x80x9calkylxe2x80x9d portion is an alkyl group as defined above, examples of such groups are methoxymethyl, ethoxymethyl, propyloxymethyl, butyloxymethyl, methoxyethyl and the like.
As used herein the term xe2x80x9csubstituted alkylxe2x80x9d refers to an alkyl group as defined above substituted by one or more substituents such as hydroxy, halogen, mercapto, sulfanyl, trihalomethyl, phenyl, substituted phenyl, heterocyclyl, substituted heterocyclyl, or C3-C7-cycloalkyl.
As used herein the term xe2x80x9calkenylxe2x80x9d refers to an unsaturated alkyl group having at least one double bond.
As used herein xe2x80x9csubstituted phenylxe2x80x9d refers to a phenyl group substituted by one or more substituents such as alkyl, alkoxy, hydroxy, amino, halogen, trihalomethyl and the like.
The term xe2x80x9csubstituted phenyloxyxe2x80x9d refers to a phenyloxy group wherein the substituents of the phenyl group are as defined above.
The term xe2x80x9chalogenxe2x80x9d refers to fluorine, chlorine, iodine or bromine.
The term xe2x80x9cheterocyclylxe2x80x9d refers to a 5 or 6-membered ring containing at least one hetero atom selected from oxygen, sulfur and nitrogen, e.g. tetrahydrofuran, pyrrolidinyl, piperidinyl, morpholinyl and the like.
The term xe2x80x9cheteroarylic ringxe2x80x9d as used herein refers to a 5 or 6-membered heteroaryl ring containing at least one hetero atom selected from oxygen, sulfur, and nitrogen for example to pyridinyl, furanyl, thiophenyl, pyrazolyl, pyrrolyl, isoxazolyl, thiazolyl, oxadiazolyl and the like; the heteroarylic ring may be substituted by alkyl.
The compounds of formula I, wherein R8 is hydrogen, form salts with pharmaceutically acceptable bases such as alkali salts, e.g. Naxe2x80x94 and K-salts, and ammonium or substituted ammonium salts such as trimethylammonium or triethylammonium salts which are within the scope of this invention.
Preferred compounds of formula I are compounds, wherein X is CR7xe2x80x2 (R7xe2x80x2 being preferably hydrogen) or nitrogen and R7 is C2-C8-alkyl, alkoxy, alkoxyalkyl, substituted alkyl, phenyloxy or substituted phenyloxy, i.e. compounds of formulae: 
wherein the symbols are as defined above.
Compounds of formula I, wherein X is xe2x80x94CHxe2x80x94 can be in the racemic form or in the (R) or (S) form.
Preferred are compounds of formula I and I-A-I-H, wherein A is xe2x80x94(CH2)xe2x80x94, n is 2, B is a group C(R3R4) and wherein Ar is phenyl with the xe2x80x94COOR8 group in position 4.
An especially preferred embodiment of the invention are the compounds of formula I-A, wherein A is xe2x80x94(CH2)xe2x80x94, n is 2, B is a group C(R3R4), Ar is phenyl with the xe2x80x94COOR8 group is in position 4 and R7xe2x80x2 is C2-C8-alkyl, alkyloxy, alkoxyalkyl or substituted alkyl such as phenyl-methyl (xe2x95x90benzyl), 2-phenyl-ethyl, p-trifluoromethylphenyl-methyl, p-chlorophenyl-methyl and the like; or phenyloxy or substituted phenyloxy.
Such especially preferred compounds are e.g.
(RS)-4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-heptanoyloxy]-benzoic acid;
(RS)-4-[3-phenyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-propanoyloxy]-benzoic acid;
(RS)-4-[4-phenyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthale-2-yl)-butanoyloxy]-benzoic acid;
(RS)-4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-3-(4-trifluoromethylphenyl)-propanoyloxy]-benzoic acid;
(RS)-4-[4-ethoxy-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-butanoyloxy]-benzoic acid;
(RS)-4-[3-(4-chlorophenyl)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-propanoyloxy]-benzoic acid;
(RS)-4-[butoxy-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-acetoxy]-benzoic acid;
(RS)-4-[methoxy-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-acetoxy]-benzoic acid;
(RS)-4-[ethoxy-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-acetoxy]-benzoic acid;
(RS)-4-[propoxy-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-acetoxy]-benzoic acid;
(R)- and (S)-4-[butoxy-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-acetoxy]-benzoic acid;
R,S)-4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-p-tolyloxy-acetoxy]-benzoic acid;
(RS)-4-[3-(4-fluorophenyl)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-propanoyloxy]-benzoic acid; and
RS)-4-[3-(3-fluorophenyl)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-propanoyloxy]-benzoic acid.
Further preferred are compounds of formula I-A wherein A is xe2x80x94(CH2)xe2x80x94 and B is oxygen, e.g.,
(R,S)-4-[2-(4,4-dimethyl-chroman-6-yl)-heptanoyloxy]-benzoic acid.
A further preferred embodiment are compounds of formula I-B, wherein A is xe2x80x94(CH2)xe2x80x94,n is 2, B is a group C(R3R4), Ar is phenyl with the xe2x80x94COOR8 group in position 4 and R7 is alkyl, alkyloxy, alkoxyalkyl or substituted alkyl such as phenyl-methyl (benzyl), 2-phenyl-ethyl, p-trifluoromethylphenyl-methyl, p-chlorophenyl-methyl and the like; or phenyloxy or substituted phenyloxy. Such especially preferred compounds are
(RS)-(E)-4-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-oct-1-enyl]-benzoic acid;
(RS)-(E)-4-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-but-1-enyl]-benzoic acid;
(RS)-(E)-4-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-hex-1-enyl]-benzoic acid;
(RS)-(E)-4-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-hepta-1,5-dienyl]-benzoic acid;
(RS)-(E)-4-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-hept-1-enyl]-benzoic acid;
(RS)-(E)-4-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-undec-1-enyl]-benzoic acid;
(RS)-(E)-4-[5-methyl-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-hex-1-enyl]-benzoic acid;
(RS)-(E)-4-[4-phenyl-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-but-1-enyl]-benzoic acid;
(RS)-(E)-4-[4-(4-chlorophenyl)-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-but-1-enyl]-benzoic acid;
(RS)-(E)-4-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-4-(4-trifluoromethylphenyl)-but-1-enyl]-benzoic acid;
(RS)-(E)-4-[5-phenyl-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-pent-1-enyl]-benzoic acid;
(RS)-(E)-5-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-oct-1-enyl]-thiophene-2-carboxylic acid;
(RS)-4-[3-butoxy-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-propenyl]-benzoic acid;
(RS)-4-[3-benzyloxy-3-(5,5,8,8-tetramethyl-5-6-7-8-tetrahydro-naphthalen-2-yl)-propenyl]-benzoic acid;
(RS)-(E)-4-[4-(4-fluorophenyl)-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-but-1-enyl]-benzoic acid;
(RS)-(E)-4-[4-(3-chlororophenyl)-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-but-1-enyl]-benzoic acid;
(RS)-(E)-4-[4-(4-methoxyphenyl)-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-but-1-enyl]-benzoic acid;
(RS)-(E)-3-fluoro-4-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-oct-1-enyl]-benzoic acid;
(E)-4-[3-methyl-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-but-1-enyl]-benzoic acid;
(E)-4-[3-ethyl-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-pent-1-enyl]-benzoic acid;
(E)-4-[3-propyl-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-hex-1-enyl]-benzoic acid;
(R,S)-4-[3-(4-chloro-phenoxy)-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-propenyl]-benzoic acid;
(R,S)-4-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-3-(4-trifluoromethyl-phenoxy)-propenyl]-benzoic acid;
(R,S)-4-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-3-p-tolyloxy-propenyl-benzoic acid; and
(R,S)-4-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-3-(4-methoxy-phenoxy)-propenyl]-benzoic acid.
Further preferred are compounds of fomula I-B wherein A is xe2x80x94(CH2)xe2x80x94, n is 2 and B is sulfur, xe2x80x94S(O)2xe2x80x94 or oxygen, e.g.,
[(RS)-(E)-4-[3-(4,4-dimethyl-thiochroman-6-yl)-oct-1-enyl]-benzoic acid];
(RS)-(E)-4-[3-(4,4-dimethyl-thiochroman-6-yl)-4-phenylbut-1-enyl]-benzoic acid;
(RS)-(E)-4-[3-(4,4-dimethyl-1,1-dioxide-thiochroman-6-yl)-oct-1-enyl]-benzoic acid;
(RS)-(E)-4-[3-(4,4-dimethyl-thiochroman-6-yl)-5-phenylpent-1-enyl]-benzoic acid; and
(R,S)-4-[3-(4,4-dimethyl-chroman-6-yl)-oct-1-ethyl]-benzoic acid.
A further preferred embodiment are compounds of formula I-D, wherein A is xe2x80x94(CH2)xe2x80x94, n is 2 and B is xe2x80x94(CR3R4)xe2x80x94, for example,
(RS)-4-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-oct-1-yl]-benzoic acid.
Further preferred are compounds of fomula I-G, wherein A is xe2x80x94(CR5R6)xe2x80x94, n is 2 and B is xe2x80x94(CR3R4)xe2x80x94 for example,
4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-ethyloxy]-benzoic acid;
(R)-4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-heptyloxy]-benzoic acid;
(S)-4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-heptyloxy]-benzoic acid;
4-[2-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-propyloxy]-benzoic acid;
4-[2-propyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-pentyloxy]-benzoic acid;
4-[1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-cyclopentyl-methoxy]-benzoic acid;
4-[1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-cyclohexyl-methoxy]-benzoic acid;
(RS)-4-[3-(pyridin-2-yl)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-propyloxy]-benzoic acid;
(RS)-4-[3-(pyridin-3-yl)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-propyloxy]-benzoic acid;
(RS)-4-[3-(pyridin-4-yl)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-propyloxy]-benzoic acid;
(RS)-4-[4-(pyridin-2-yl)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-butyloxy]-benzoic acid;
RS)-4-[4-(pyridin-3-yl)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-butyloxy]-benzoic acid;
(RS)-4-[4-(pyridin-4-yl)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-butyloxy]-benzoic acid;
(RS)-4-[3-(1-pyrazol-1-yl)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-propyloxy]-benzoic acid;
(RS)-4-[4-(pyrazol-1-yl)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-butyloxy]-benzoic acid;
(RS)-4-[4-(pyrrol-1-yl)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-butyloxy]-benzoic acid;
(RS)-4-[3-(5-methyl-isoxazol-2-yl)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-propyloxy]-benzoic acid;
(RS)-4-[3-(2-methyl-thiazol-4-yl)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-propyloxy]-benzoic acid;
(RS)-4-[3-(1,2,4-oxadiazol-3-yl)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-propyloxy]-benzoic acid;
(RS)-4-[3-(furan-2-yl)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-propyloxy]-benzoic acid;
(RS)-4-[3-(tetrahydrofuran-2-yl)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-propyloxy]-benzoic acid;
(RS)-4-[3-(cyclohexyl)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-propyloxy]-benzoic acid;
(RS)-4-[6-hydroxy-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-hexyloxy]-benzoic acid; and
(RS)-4-[4-thioethyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-butyloxy]-benzoic acid;
and compounds of formula I-G, wherein A is xe2x80x94(CR5R6), n is 2 and B is oxygen, N-alkyl or S(O)m, m being 0 or 1, such compounds as for example,
(RS)-4-[2-(N-ethyl-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)-heptyloxy]-benzoic acid;
(RS)-4-[2-(4,4-dimethyl-thiochroman-6-yl)-heptyloxy]-benzoic acid;
(RS)-4-[2-(4,4-dimethyl-1-oxide-thiochroman-6-yl)-heptyloxy]-benzoic acid; and
(RS)-4-[2-(2,2,4,4-tetramethyl-chroman-6-yl)-heptyloxy]-benzoic acid.
A further preferred embodiment are compounds of formula I-C, wherein A is xe2x80x94(CH2)xe2x80x94, n is 2, B is a group C(R3R4), Ar is phenyl with the xe2x80x94COOR8 group is in position 4 and R7 is phenyloxy or substituted phenyloxy.
A further preferred embodiment are compounds of formula I-F, wherein A is xe2x80x94(CH2)xe2x80x94, n is 2, B is a group C(R3R4), Ar is phenyl with the COOR8 group is in position 4 and R7 is alkyl, alkoxyalkyl or substituted alkyl such as phenyl-methyl (benzyl), 2-phenyl-ethyl, p-trifluoromethylphenyl-methyl, p-chlorophenyl-methyl and the like.
A further preferred embodiment are compounds of formula I-H, wherein A is xe2x80x94(CH2)xe2x80x94, n is 2, B is a group C(R3R4), Ar is phenyl with the xe2x80x94COOR8 group is in position 4 and R7 is alkyl, alkyloxy, alkoxyalkyl or substituted alkyl such as phenyl-methyl (benzyl), 2-phenyl-ethyl, p-trifluoromethylphenyl-methyl, p-chlorophenyl-methyl and the like or substituted alkoxy such as phenylmethoxy; or 2-phenylethoxy, or phenyloxy or substituted phenyloxy.
The compounds of formula I-A, wherein X is xe2x80x94CHxe2x80x94, Z is xe2x80x94COOxe2x80x94 and R7 is alkyl, alkoxyalkyl or substituted alkyl can be prepared according to the method depicted in reaction scheme 1:
wherein the symbols are as defined above.
The compounds of formula 3 are readily accessible through the general synthetic route depicted in Scheme 1. The acid 1 can be prepared according to previous published procedures (WO 92/06948). The acid 1 can be doubly deprotonated with lithiumdiisopropylamide (LDA) and the resulting dianion can be reacted with a variety of electrophiles to give alkylated products of the type 2. A coupling using N,Nxe2x80x2-dicyclohexylcarbodiimide (DCC) and 4-dimethylamino-pyridine (DMAP) with the appropriate functionalized 4-hydroxy-benzoate leads to compounds 3. Hydrolysis of the ester (R8xe2x95x90alkyl) or hydrogenolysis (R8xe2x95x90benzyl) provides the acid (R8xe2x95x90H).
The compounds of formula I-A, wherein X is xe2x80x94CHxe2x80x94, Z is xe2x80x94COOxe2x80x94 and R7 is alkoxy can be prepared according to the method depicted in reaction scheme 1a: 
wherein A, B, n, R1 and R2 are as defined above and
R and R7xe2x80x2 are, independently from each other, alkyl or substituted alkyl.
Starting compounds of formula 4 are known can be prepared by methods known in the art. The xcex1-keto-ester 5 can be synthesized by Friedel-Crafts reaction of compound 4 with ethyl oxalyl chloride/AlCl3. Other methods are described in Tetrahedron 55, 11343 (1999) by R. Rossi et al. Reduction of the ketogroup in 5 with sodium borohydride yields the 2-hydroxy-ester 6, which can be alkylated with various alkylhalogenides using silver oxide or cesium carbonate as a base to give compound 7. Another route to compound 7 is reductive alkylation of 5 according to M. Nishizawa, Tetrahedron Letters 35, 4367 (1994), using alkoxy-trimethylsilane and triethylsilane as reagents and trimethylsilyl triflate as catalyst. Hydrolysis of the ester 7 affords the acid 8, which can be transformed into compounds of formula I-A as shown in scheme 1.
Compounds of formula I-A, wherein Xxe2x95x90xe2x80x94CHxe2x80x94, Zxe2x95x90xe2x80x94COOxe2x80x94 and R7xe2x95x90phenyloxy or substituted phenyloxy can be prepared according to scheme 1b: 
wherein A, B, n, R, R1 and R2 are as defined above;
Xxe2x80x2 is halogen; and
R7xe2x80x3 is unsubstituted phenyloxy or substituted phenyloxy.
The xcex1-hydroxy-ester 6 can be transformed into the xcex1-chloro- or xcex1-bromo-ester 9 using SOCl2 or SOBr2. Reaction with a sodium phenolate affords the phenyloxy-ester 10, which can be transformed into compounds of formula I-A as shown in scheme 1.
The compounds of formula I-B, wherein X is xe2x80x94CHxe2x80x94 and Z is xe2x80x94CHxe2x95x90CHxe2x80x94 can be prepared according to the method depicted in reaction scheme 2:
wherein A, B, n, R1, R2, R7, Ar and R8 are as defined above.
The acid 2 is being reduced to the alcohol 11a then reoxydated to the aldehyde 12 in high yields (BH3.THF (tetrahydrofuran) followed by Swern oxydation). An alternative route with high yields consists of transforming the acid 2 to the Weinreb amide 11b and then reducing it with LiAlH4 to the aldehyde 12. A Wittig-Horner with the appropriate phosphonate leads to the olefin I-B. Hydrolysis of the ester then gives the corresponding acid (R8xe2x95x90H).
Compounds of the formula I-D can be obtained from intermediate I-B (R8xe2x95x90alkyl or H) by hydrogenation of the olefin. Hydrolysis (where R8xe2x95x90alkyl) under standard procedures provides the corresponding acids (R8xe2x95x90H), see Scheme 3:
wherein the symbols are as defined above.
Compounds of formula I-G and I-H can be prepared according to the method depicted in reaction scheme 4.
wherein
Z2 is oxygen or sulfur, and the remaining symbols are as defined above.
Compound 13 can be produced analogously to compound 11a, wherein R7 is defined as in formula I. The compounds 14 (where Z2 is O or S) can be synthesized by a Mitsunobu type coupling (diethyl azodicarboxylate (DEAD), Ph3P) using the appropriate phenol or thiophenol coupling partner and compound 13. Hydrolysis of the esters 14 can be accomplished using standard procedures to give the corresponding acids (R8xe2x95x90H).
Reaction scheme 5 outlines the method for the preparation of compounds of formula I-C: 
wherein the symbols are as defined above.
The aldehyde 12a is synthesized in the same manner as aldehyde 12, except that R7 is phenoxy or substituted phenoxy. Aldehyde 12a can be transformed into the acetylenic derivatives 15, using the method of Corey and Fuchs by reaction with Ph3P/CBr4 then subsequently with butyllithium (BuLi). The intermediate 15 can then be coupled with an appropriate halo aromatic ester in a Pd(0) catalyzed reaction. The resulting compounds I-C can be hydrolyzed to the acids I-C (R8xe2x95x90H) in the usual way.
Preparation of compounds of formula I-E: 
wherein the symbols are as defined above.
Compounds of the formula I-E can be synthesized according to Scheme 6, via two routes leading to intermediate 17. Bromide 16 is formed by the bromination of compound 4. The bromide 16 can be transformed into the Grignard reagent with Mg and then reacted with an aldehyde of formula R7CHO. In a second way, compound 4 can be reacted with an acid chloride (R7COCl)/AlCl3 to give the ketone 18. Reduction of the carbonyl by BH3.THF or LiAlH4 yields the alcohol 17. Coupling of the alcohol 17 with a half ester of terephthalic acid provides the compounds of formula I-E (R8xe2x95x90alkyl or benzyl). Hydrogenolysis (R8xe2x95x90benzyl) provides the corresponding acid (R8xe2x95x90H).
The compounds of formula I, wherein X is xe2x80x94CHxe2x80x94 and Z is xe2x80x94CH2COxe2x80x94 (formula 21 in scheme 7) can be prepared from the starting bromide 16, by formylation using lithium-halogen exchange/DMF. The aldehyde 19 can then be used in an aldol condensation with the substituted acetophenone. The enone 20 can be reacted with the appropriate cuprate or mixed cuprate to yield 21. Hydrolysis (R8xe2x95x90alkyl) or hydrogenolysis (R8xe2x95x90benzyl) provides the acid 21 (R8xe2x95x90H). 
wherein the symbols are as defined above.
Compounds of formula I, wherein X is xe2x80x94CHxe2x80x94 and Z is xe2x80x94COCH2xe2x80x94 can be prepared as described in reaction scheme 8. The aldehyde 12 can be converted to the dithiane 22 under standard procedures. The anion of 22 (from 22 and BuLi) is then trapped with the benzyl bromide bearing a protected or masked carboxyl group. Deprotection of the dithiane with Hg (ClO4)2 provides the carbonyl compound 23. Hydrolysis under standard conditions gives the keto acid 23, (R8xe2x95x90H). See scheme 8:
wherein the symbols are as defined above.
Compounds of formula I, wherein X is nitrogen and Z is xe2x80x94COOxe2x80x94, i.e. compounds of formula I-F can be prepared according to scheme 9:
wherein the symbols are as defined above.
Compound 24 can be formed from compound 4 by methods known in the art. Monoalkylation of amine 24 (e.g. via the trifluoroacetylamide, alkylation using KOH/DMSO and hydrolysis) affords compound 25, which is chloroformylated with phosgene or triphosgene to give compound 26. Reaction with 4-hydroxy-benzoate (R8xe2x95x90benzyl) and pyridine yields compound 27, which can be hydrogenated to give compound of formula I-F.
Further preferred compounds of formula I are those of formula I-J 
wherein
R1, R2, R3 and R4 independently of each other are hydrogen or lower alkyl;
Z is xe2x80x94OCH2xe2x80x94 or xe2x80x94SCH2xe2x80x94,
Y is xe2x80x94CR7xe2x80x2R7xe2x80x2xe2x80x94, and
each R7xe2x80x2 is independently hydrogen, alkyl, alkenyl, alkoxy, alkoxyalkyl, substituted alkyl, phenyloxy or substituted phenyloxy, or both R7xe2x80x2 together are xe2x80x94(CH2)pxe2x80x94, where p is 2-6; or
Z is xe2x80x94Cxe2x89xa1Cxe2x80x94,
Y is xe2x80x94CR7xe2x80x2R7xe2x80x3,
R7xe2x80x2 is hydrogen, alkyl, alkenyl, alkoxy, alkoxyalkyl, substituted alkyl, phenyloxy or substituted phenyloxy, and
R7xe2x80x3 is phenoxy or substituted phenoxy; or
Z is xe2x80x94COOxe2x80x94, xe2x80x94OCOxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2Oxe2x80x94, xe2x80x94CH2Sxe2x80x94, xe2x80x94COCH2xe2x80x94 or xe2x80x94CH2COxe2x80x94, and
Y is Nxe2x80x94R7, wherein R7 is alkyl, alkoxyalkyl or substituted alkyl, or
Y is xe2x80x94CR7xe2x80x2R7xe2x80x2, wherein each R7xe2x80x2 is independently hydrogen, alkyl, alkenyl, alkoxy, alkoxyalkyl, substituted alkyl, phenyloxy or substituted phenyloxy, or both R7xe2x80x2 together are xe2x80x94(CH2)pxe2x80x94, where p is 2-6;
Ar is phenyl, substituted phenyl or a heteroarylic ring; and
R8 is hydrogen, lower alkyl or benzyl;
and pharmaceutically acceptable salts of carboxylic acids of formula I-J.
Still further preferred compounds of formula I are those of formula I-K 
wherein
B is C(R3R4), oxygen, S(O)m or N-alkyl and
m is 0, 1 or 2;
R1, R2,R3, R4, R5 and R6 independently of each other are hydrogen or lower alkyl;
Z is xe2x80x94OCH2xe2x80x94 or xe2x80x94SCH2xe2x80x94,
Y is xe2x80x94CR7xe2x80x2R7xe2x80x2xe2x80x94, and
each R7xe2x80x2 is independently hydrogen, alkyl, alkenyl, alkoxy, alkoxyalkyl, substituted alkyl, phenyloxy or substituted phenyloxy, or both R7xe2x80x2 together are xe2x80x94(CH2)pxe2x80x94, where p is 2-6; or
Z is xe2x80x94Cxe2x89xa1Cxe2x80x94,
Y is xe2x80x94CR7xe2x80x2R7xe2x80x3,
R7xe2x80x2 is hydrogen, alkyl, alkenyl, alkoxy, alkoxyalkyl, substituted alkyl, phenyloxy or substituted phenyloxy, and
R7xe2x80x3 is phenoxy or substituted phenoxy; or
Z is xe2x80x94COOxe2x80x94, xe2x80x94OCOxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2Oxe2x80x94, xe2x80x94CH2Sxe2x80x94, xe2x80x94COCH2xe2x80x94 or xe2x80x94CH2COxe2x80x94, and
Y is Nxe2x80x94R7, wherein R7 is alkyl, alkoxyalkyl or substituted alkyl, or
Y is xe2x80x94CR7xe2x80x2R7xe2x80x2xe2x80x94, wherein each R7xe2x80x2 is independently hydrogen, alkyl, alkenyl, alkoxy, alkoxyalkyl, substituted alkyl, phenyloxy or substituted phenyloxy, or both R7xe2x80x2 together are xe2x80x94(CH2)pxe2x80x94, where p is 2-6;
Ar is phenyl, substituted phenyl or a heteroarylic ring; and
R8 is hydrogen, lower alkyl or benzyl;
and pharmaceutically acceptable salts of carboxylic acids of formula I-K.
Preferred compounds of formula I-K are those wherein B is C(R3R4), R5 and R6 are H, and Ar is phenyl or substituted phenyl. Within these preferred compounds of formula I-K, most preferred are those wherein Y is xe2x80x94CR7xe2x80x2R7xe2x80x2xe2x80x94 and Z is selected from the group xe2x80x94COOxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94 and xe2x80x94CH2Oxe2x80x94.
Further preferred compounds of formula I-K are those wherein B is O, R5 and R6 are H, and Ar is phenyl or substituted phenyl. Within these preferred compounds of formula I-K, most preferred are those wherein Y is xe2x80x94CR7xe2x80x2R7xe2x80x2xe2x80x94 and Z is selected from the group xe2x80x94COOxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94 and xe2x80x94CH2Oxe2x80x94.
Still other preferred compounds of formula I-K are those wherein B is S(O)m, R5 and R6 are H, and Ar is phenyl or substituted phenyl. Within these preferred compounds of formula I-K, most preferred are those wherein Y is xe2x80x94CR7xe2x80x2R7xe2x80x2xe2x80x94 and Z is xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94CH2Oxe2x80x94.
Still other preferred compounds of formula I-K are those wherein B is N-alkyl, R5 and R6 are H, and Ar is phenyl or substituted phenyl.
Other preferred compounds of formula I are those of formula I-L 
wherein
R1, R2, R3 and R4 independently of each other are hydrogen or lower alkyl;
Z is xe2x80x94OCH2xe2x80x94 or xe2x80x94SCH2xe2x80x94,
Y is xe2x80x94CR7xe2x80x2R7xe2x80x2xe2x80x94, and
each R7xe2x80x2 is independently hydrogen, alkyl, alkenyl, alkoxy, alkoxyalkyl, substituted alkyl, phenyloxy or substituted phenyloxy, or both R7xe2x80x2 together are xe2x80x94(CH2)pxe2x80x94, where p is 2-6; or
Z is xe2x80x94Cxe2x89xa1Cxe2x80x94,
Y is xe2x80x94CR7xe2x80x2R7xe2x80x3,
R7xe2x80x2 is hydrogen, alkyl, alkenyl, alkoxy, alkoxyalkyl, substituted alkyl, phenyloxy or substituted phenyloxy, and
R7xe2x80x3 is phenoxy or substituted phenoxy; or
Z is xe2x80x94COOxe2x80x94, xe2x80x94OCOxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94,xe2x80x94CH2Oxe2x80x94, xe2x80x94CH2Sxe2x80x94, xe2x80x94COCH2xe2x80x94 or xe2x80x94CH2COxe2x80x94, and
Y is Nxe2x80x94R7, wherein R7 is alkyl, alkoxyalkyl or substituted alkyl, or Y is xe2x80x94CR7xe2x80x2R7xe2x80x2xe2x80x94, wherein each R7xe2x80x2 is independently hydrogen, alkyl, alkenyl, alkoxy, alkoxyalkyl, substituted alkyl, phenyloxy or substituted phenyloxy, or both R7xe2x80x2 together are xe2x80x94(CH2)pxe2x80x94, where p is 2-6;
Ar is phenyl, substituted phenyl or a heteroarylic ring; and
R8 is hydrogen, lower alkyl or benzyl;
and pharmaceutically acceptable salts of carboxylic acids of formula I-L.
Preferred compounds of formula I-L are those wherein B is C(R3R4), R5 and R6 are H and Ar is phenyl or substituted phenyl.
Other preferred compounds of formula I-L are those wherein B is oxygen, S(O)m or N-alkyl; R5 and R6 are H and Ar is phenyl or substituted phenyl.
Still other preferred compounds of formula I are those of formula I-M 
wherein
B is C(R3R4), oxygen, S(O)m or N-alkyl and
m is 0, 1 or 2;
R1, R2,R3, R4, R5 and R6 independently of each other are hydrogen or lower alkyl;
Z is xe2x80x94OCH2xe2x80x94 or xe2x80x94SCH2xe2x80x94,
Y is xe2x80x94CR7xe2x80x2R7xe2x80x2xe2x80x94, and
each R7xe2x80x2 is independently hydrogen, alkyl, alkenyl, alkoxy, alkoxyalkyl, substituted alkyl, phenyloxy or substituted phenyloxy, or both R7xe2x80x2 together are xe2x80x94(CH2)pxe2x80x94, where p is 2-6; or
Z is xe2x80x94Cxe2x89xa1Cxe2x80x94,
Y is xe2x80x94CR7xe2x80x2R7xe2x80x3,
R7xe2x80x2 is hydrogen, alkyl, alkenyl, alkoxy, alkoxyalkyl, substituted alkyl, phenyloxy or substituted phenyloxy, and
R7xe2x80x3 is phenoxy or substituted phenoxy; or
Z is xe2x80x94COOxe2x80x94, xe2x80x94OCOxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2Oxe2x80x94, xe2x80x94CH2Sxe2x80x94, xe2x80x94COCH2xe2x80x94 or xe2x80x94CH2COxe2x80x94, and
Y is Nxe2x80x94R7, wherein R7 is alkyl, alkoxyalkyl or substituted alkyl, or
Y is xe2x80x94CR7xe2x80x2R7xe2x80x2xe2x80x94, wherein each R7xe2x80x2 is independently hydrogen, alkyl, alkenyl, alkoxy, alkoxyalkyl, substituted alkyl, phenyloxy or substituted phenyloxy, or both R7xe2x80x2 together are xe2x80x94(CH2)pxe2x80x94, where p is 2-6;
Ar is phenyl, substituted phenyl or a heteroarylic ring; and
R8 is hydrogen, lower alkyl or benzyl;
and pharmaceutically acceptable salts of carboxylic acids of formula I-M.
Preferred compounds of formula I-M are those wherein B is C(R3R4), R5 and R6 are H and Ar is phenyl or substituted phenyl.
Other preferred compounds of formula I-M are those wherein B is oxygen, S(O)m or N-alkyl; R5 and R6 are H and Ar is phenyl or substituted phenyl.
In another aspect, this invention is concerned with the use of RAR selective agonist with systemic administration being a preferred mode of delivery for treating emphysema and associated pulmonary diseases. It is thus concerned with a method for treating emphysema and associated pulmonary diseases by treatment of a mammal with a RAR selective agonist with systemic administration being a preferred mode of delivery.
A xe2x80x9ctherapeutically effective amountxe2x80x9d means the amount of a compound that, when administered to a mammal for treating or preventing a disease, is sufficient to effect such treatment or prevention for the disease. The xe2x80x9ctherapeutically effective amountxe2x80x9d will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
The RARxcex3 agonist selectivity of a compound can be determined by routine ligand binding assays known to one skilled in the art such as described in C. Apfel et al. Proc. Nat. Sci. Acad. (USA), 89:7129-7133 (1992); M. Teng et al., J. Med. Chem., 40:2445-2451 (1997); and PCT Publication WO 96/30009.
The uses of the RAR agonists of formulae I-A through I-M disclosed herein may be used for promoting the repair of damaged alveoli and septation of new alveoli, particularly for the treatment emphysema. Treatment with RAR agonists, particularly, RARxcex3 selective agonists is useful to promote repair of alveolar matrix and septation. As such, the methods disclosed herein are useful for treating diseases such as emphysema.
Typically, the dosage will range between about 0.01 and 1.0 mg/kg body weight per day, preferably from about 0.05 to about 0.5 mg/kg body weight per day.
In particular dosage of a RAR selective agonist required to treat lung emphysema will depend on the severity of the condition. This dosage may be delivered in a conventional pharmaceutical composition by a single administration, by multiple applications, or via controlled release, as needed to achieve the most effective results. Dosing will continue for as long as is medically indicated, which depending on the severity of the disease may range from a few weeks to several months.
Typically, a pharmaceutically acceptable composition, such as a salt, of the RAR agonist of formula I in a pharmaceutically acceptable carrier or diluent is administered. In the context of the present invention, pharmaceutically acceptable salts include any chemically suitable salt known in the art of retinoid agonists as applicable for administration to human patients. Examples of conventional salts known in the art include the alkali metal salts such as sodium and potassium salts, the alkaline earth metal salts such as calcium and magnesium salts, and ammonium and alkyl ammonium salts.
Representative delivery regimens include oral, parenteral (including subcutaneous, intramuscular and intravenous), rectal, buccal (including sublingual), transdermal, pulmonary and intranasal. One method of pulmonary administration involves aerosolization of a solution of an RAR agonist. Aerosolized compositions may include the compound packaged in reverse micelles or liposomes. Typical pulmonary and respiratory delivery systems are described in U.S. Pat. Nos. 5,607,915, 5,238,683, 5,292,499, and 5,364,615.
The treatment methods of this invention also include systemic administration of RAR agonists in simultaneous or sequential combination with a further active ingredient.
RAR agonists will typically be administered as pharmaceutical compositions in admixture with a pharmaceutically acceptable, non toxic carrier. As mentioned above, such compositions may be prepared for parenteral (subcutaneous, intramuscular or intravenous) administration, particularly in the form of liquid solutions or suspensions; for oral or buccal administration, particularly in the form of tablets or capsules; for intranasal administration, particularly in the form of powders, nasal drops or aerosols; and for rectal or transdermal administration. Any conventional carrier material can be employed. The carrier material can be any organic or inorganic carrier material, such as water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, polyalkylene glycols, petroleum jelly and the like.
Liquid formulations for parenteral administration may contain as excipients sterile water or saline, alkylene glycols such as propylene glycol, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like. They may employ slightly acidic buffers in pH ranges of about 4 to about 6. Suitable buffers include acetate, ascorbate and citrate at concentrations ranging from about 5 mM to about 50 mM. For oral administration, the formulation can be enhanced by the addition of bile salts or acylcarnitines.
Formulations for nasal administration may be solid and may contain excipients, for example, lactose or dextran, or may be aqueous or oily solutions for use in the form of nasal drops or metered spray. Particular nasal formulations include dry powders suitable for conventional dry powder inhalers (DPI""s), liquid solutions or suspensions suitable for nebulization and propellant formulations suitable for use in metered dose inhalers (MDI""s). For buccal administration typical excipients include sugars, calcium stearate, magnesium stearate, pregelatinated starch, and the like.
When formulated for nasal administration, the absorption across the nasal mucous membrane may be enhanced by surfactant acids, such as for example, glycocholic acid, cholic acid, taurocholic acid, ethocholic acid, deoxycholic acid, chenodeoxycholic acid, dehydrocholic acid, glycodeoxycholic acid, cyclodextrins and the like in an amount in the range between about 0.2 and 15 weight percent, preferably between about 0.5 and 4 weight percent, most preferably about 2 weight percent.
Solid forms for oral administration include tablets, hard and soft gelatin capsules, pills, sachets, powders, granules and the like. Each tablet, pill or sachet may contain from about 1 to about 50 mg, preferably from 5 to about 10 mg of RAR agonist. Preferred solid oral dosage forms include tablets, two-piece hard shell capsules and soft elastic gelatin (SEG) capsules. SEG capsules are of particular interest because they provide distinct advantages over the other two forms (see Seager, H., xe2x80x9cSoft gelatin capsules: a solution to many tableting problemsxe2x80x9d; Pharmaceutical Technology, 9, (1985). Some of the advantages of using SEG capsules are: a) dose-content uniformity is optimized in SEG capsules because the drug is dissolved or dispersed in a liquid that can be dosed into the capsules accurately b) drugs formulated as SEG capsules show good bioavailability because the drug is dissolved, solubilized or dispersed in an aqueous-miscible or oily liquid and therefore when released in the body the solutions dissolve or are emulsified to produce drug dispersions of high surface area and c) degradation of drugs that are sensitive to oxidation during long-term storage is prevented because of the dry shell.
Delivery of the compounds of the present invention to the subject over prolonged periods of time, for example, for periods of one week to one year, may be accomplished by a single administration of a controlled release system containing sufficient active ingredient for the desired release period. Various controlled release systems, such as monolithic or reservoir type microcapsules, depot implants, osmotic pumps, vesicles, micelles, liposomes, transdermal patches, iontophoretic devices and alternative injectable dosage forms may be utilized for this purpose. Localization at the site to which delivery of the active ingredient is desired is an additional feature of some controlled release devices, which may prove beneficial in the treatment of certain disorders.
The following are representative pharmaceutical formulations for using RAR selective agonists as described herein for promoting elastin mediated matrix repair and alveolar septation.
Tablet Formulation
The following ingredients are mixed intimately and pressed into single scored tablets.
Capsule Formulation
The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule.
Suspension Formulation
The following ingredients are mixed to form a suspension for oral administration.
Injectable Formulation
The following ingredients are mixed to form an injectable formulation.
Nasal Formulation
The following ingredients are mixed to form a suspension for nasal administration.
The following preparations and examples are given to enable those skilled in the art to more clearly understand and to practice the present invention.